Original
Effect of cimetidine, a model drug for inhibition of the organic cation transport (OCT2/MATE1) in the kidney, on the pharmacokinetics of glycopyrronium
Swati Dumitras, Romain Sechaud, Anton Drollmann, Parasar Pal, Sivakumar Vaidyanathan, Gian Camenisch and Guenther Kaiser
Price
42.00 $
Volume 51 p. 771 - 779
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 10/2013 (771-779)
Effect of cimetidine, a model drug for inhibition of the organic cation transport (OCT2/MATE1) in the kidney, on the pharmacokinetics of glycopyrronium
Swati Dumitras1, Romain Sechaud1, Anton Drollmann2, Parasar Pal4, Sivakumar Vaidyanathan3, Gian Camenisch1 and Guenther Kaiser1
1Drug Metabolism and Pharmacokinetics, 2Translational Medicine, Novartis Institutes for BioMedical Research, Basel, Switzerland, 3Translational Medicine, Novartis Institutes for BioMedical Research, and 4Integrated Information Sciences, Novartis Healthcare Private Limited, Hyderabad, India
Objective: Glycopyrronium (NVA237), a novel once-daily long-acting muscarinic antagonist (LAMA), has recently been approved for maintenance treatment of COPD. This study evaluated the effect of organic cation transporter inhibition on inhaled glycopyrronium disposition using cimetidine as a probe inhibitor. Methods: In this open-label, two-period, two-sequence, crossover study, 20 healthy subjects received two treatments. A single dose of 100 μg glycopyrronium was inhaled alone and on Day 4 of a 6-day treatment with oral cimetidine 800 mg b.i.d. Trough plasma concentrations of cimetidine were determined throughout cimetidine dosing. Plasma concentrations and urinary excretion of glycopyrronium were determined up to 72 hours post glycopyrronium dose. The primary pharmacokinetics (PK) parameters were plasma peak concentration (Cmax), AUC up to the last measured concentration (AUClast), and renal clearance (CLr) of glycopyrronium. Results: Cimetidine trough concentrations indicated that PK steady state of cimetidine was reached prior to single dose inhalation of glycopyrronium. Inhalation of glycopyrronium in the presence of cimetidine resulted in an increase in total systemic exposure (AUClast) of glycopyrronium by 22% (geometric mean ratio 1.22; 90% CI: 1.12 – 1.32). This exposure increase correlated with a slight decrease of 23% in CLr (geometric mean ratio 0.77; 90% CI: 0.70 – 0.85). Cmax was not affected. Both treatments were safe and well tolerated without any deaths or severe adverse events. Conclusion: Based on the magnitude of the PK changes seen in this study, no relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport.Correspondence to:
Dr. Swati Dumitras, Senior Investigator I
Drug Metabolism Pharmacokinetics
Novartis Institute of BioMedical Research
Basel, Switzerland
Email: [email protected]
Original Research
Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three- period, cross-over, placebo- and positive-controlled study
Anton Drollmann, Romain Sechaud, Parasar Pal, Hisanori Hara, Susan Uziel-Fusi, and Peter Winkle
Price
42.00 $
Volume 52 p. 739 - 745
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 9/2014 (739-745)
Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three- period, cross-over, placebo- and positive-controlled study
Anton Drollmann1, Romain Sechaud1, Parasar Pal2, Hisanori Hara1, Susan Uziel-Fusi3, and Peter Winkle4
1Novartis Institutes for BioMedical Research, Basel, Switzerland, 2Integrated Information and Sciences, Novartis Healthcare Private Ltd, Hyderabad, India, 3Novartis Pharmaceutical Corporation, East Hanover, NJ, and 4Advanced Clinical Research Institute, Anaheim, CA, USA
Objective: Glycopyrronium (NVA237), a once-daily long-acting muscarinic antagonist, has recently been approved for the treatment of patients with chronic obstructive pulmonary disease (COPD). This study evaluated the effect of glycopyrronium on the QT interval and other cardiac parameters in healthy subjects. Methods: This randomized, partially blinded, single-dose, placebo- and positive- (moxifloxacin) controlled, three-way cross-over study investigated the effect of a single inhaled supra-therapeutic dose (8-fold clinical dose in COPD patients) of 400 μg glycopyrronium on the Fridericia-corrected QT interval (QTcF; primary objective), Bazettcorrected QT interval (QTcB), heart rate, blood pressure, pharmacokinetics (PK), safety, and tolerability. Results: A total of 73 healthy male (n = 35) and female (n = 38) subjects, aged between 18 and 45 years, were randomized. Glycopyrronium did not cause significant QTcF prolongation compared to placebo. The largest time-matched mean difference to placebo was 2.97 ms at 5 minutes, with the upper limit of the two-sided 90% confidence interval (CI) being 4.80 ms, excluding a relevant QT effect as defined by the ICH E14 guideline. Glycopyrronium had a slight bradycardic effect with a mean change of –2.88 (90% CI: –3.78, –1.99) beats per minutes (bpm) and a maximum of –5.87 (90% CI: –7.82, –3.92) bpm at 5 hours post-inhalation. No clinically relevant effects were seen on QTcB, other electrocardiogram (ECG) intervals, or blood pressure. Maximum plasma concentration (Cmax) of glycopyrronium was achieved shortly after inhalation (median tmax = 7 minutes). All the treatments were well tolerated with no serious adverse events. Conclusion: A supra-therapeutic dose of glycopyrronium had a favorable cardiovascular safety profile with no clinically relevant effect on QT interval.Correspondence to:
Dr. Anton Drollmann, Executive Director
Translational Medicine- Respiratory Profiling Head
Novartis Pharma AG, Building WSJ 386.12.48.50
Postfach, 4002 Basel, Switzerland
Email: [email protected]
Bioavailability Section
Effect of food on the oral bioavailability of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects
Surya Ayalasomayajula, Thomas Langenickel, Priya Chandra, Edward Wolfson, Diego Albrecht, Wei Zhou, Parasar Pal, Iris Rajman, Gangadhar Sunkara
Price
42.00 $
Volume 54 p. 1012 - 1018
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 12/2016 (1012-1018)
Effect of food on the oral bioavailability of the angiotensin receptor - neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects
Surya Ayalasomayajula1, Thomas Langenickel2, Priya Chandra1, Edward Wolfson3, Diego Albrecht2, Wei Zhou1, Parasar Pal4, Iris Rajman2, Gangadhar Sunkara1
1Novartis Institutes for BioMedical Research, East Hanover, NJ, USA,
2Novartis Institutes for BioMedical Research, Basel, Switzerland,
3Novartis Institutes for BioMedical Research, Cambridge, MA, USA, and 4Biostatistical Sciences, Novartis Healthcare Pvt. Ltd., Hyderabad, India
Objective: Sacubitril/valsartan (LCZ696) provides a novel therapeutic approach of neurohormonal modulation in heart failure via simultaneous inhibition of neprilysin and blockade of the angiotensin II type-1 receptor. This study was conducted to evaluate the effect of food on the oral bioavailability of LCZ696 analytes. Materials and methods: This was an open-label, randomized, 3-period crossover study in healthy subjects. Eligible subjects (N = 36) were randomized to 6 treatment sequences, each comprising 3 treatment periods during which subjects received a single oral dose of 400 mg LCZ696 under fasting condition and following a low- and high-fat meal. Results: Following administration of LCZ696 after low- and high-fat meals, the mean Cmax of sacubitril and sacubitrilat (the active neprilysin inhibitor) decreased by 42 – 54% and 19 – 28%, respectively, while the tmax values increased. However, systemic exposure (AUCinf and AUClast) of sacubitril was slightly decreased (by 16% with low-fat meal) and that of sacubitrilat was unchanged in the presence of food. For valsartan, the Cmax decreased by ~ 40% when LCZ696 was administered after low- and high-fat meals. The systemic exposure of valsartan decreased by ~ 33% with a low-fat meal; however, it was unchanged with a high-fat meal. LCZ696 was generally safe and well tolerated in healthy subjects when administered under fasting or fed condition. Conclusion: Overall, administration of LCZ696 with meals decreased the rate and extent of absorption of sacubitril with little impact on the systemic exposure to sacubitrilat, its active metabolite. The systemic exposure to valsartan was decreased in the presence of food.
Correspondence to:
Surya Ayalasomayajula, MS, PhD
Novartis Institutes for Biomedical Research
East Hanover, NJ, USA
Email: surya.ayalasomayajula@ novartis.com
Original Research
Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment
Kenneth M. Kulmatycki, Thomas Langenickel, Wai Hong Ng, Parasar Pal, Wei Zhou, Tsu-Han Lin, Iris Rajman, Priyamvada Chandra, and Gangadhar Sunkara
Price
42.00 $
Volume 55 (2017) p. 728 - 739
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 9/2017 (728-739)
Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment
Kenneth M. Kulmatycki1, Thomas Langenickel2, Wai Hong Ng3, Parasar Pal4, Wei Zhou3, Tsu-Han Lin3, Iris Rajman2, Priyamvada Chandra3, and Gangadhar Sunkara3
1Novartis Institutes for Biomedical Research, Cambridge, MA, USA, 2Novartis Institutes for BioMedical Research, Basel, Switzerland,
3Novartis Institutes for Biomedical Research, East Hanover, NJ, USA, and
4Novartis Healthcare Pvt. Ltd., Hyderabad, Telangana, India
Objectives: To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. Methods: This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. Results: Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 – 109%, respectively. Conclusions: The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups.
Correspondence to:
Kenneth M. Kulmatycki, PhD
Novartis Institutes for Biomedical Research
220 Massachusetts Avenue, 342E
Cambridge, MA 02139, USA
Email: [email protected]
